The Program Project represents a comprehensive collaborative effort by eight senior investigators in two Departments and two different Colleges at the University of Arizona to carry out an extensive, systematic investigation for the development of novel opioid ligands and opioid/substance P (CGRP) chimeric ligands, and for obtaining an understanding of the biochemical/physiological basis of tolerance that will lead to novel methods for the treatment of pain, and new ligands that will provide new modalities for treatment of pain without the toxic side effects of current opioids used in clinical medicine such as respiratory depression and tolerance. The observation that during extended use opioid drugs cause pain have led us to consider novel hypotheses to obtain an understanding of these effects and to develop ligands that can address the system changes in severe pain states with new modalities of treatment. New methods of drug design and new understandings of underlying physiological/biochemical mechanism related to pain and to paradoxical opioid induced pain will be critical to the long-term goals of this Program Project Grant. A highly cooperative and collaborative multi-disciplinary approach involving computer aided drug design; asymmetric synthesis; biophysics; binding studies at several receptors; in vitro and in vivo bioassays; molecular biology, and examination of second messenger and other aspects of signal transduction, have been established. We will develop new asymmetric synthesis of novel constrained amino acids; new methods to prepare beta-turn mimetics; use of computational chemistry in design of ligands and modeling of receptors; design of novel constrained bioactive ligands and chimeric ligands that interact with two or more receptors in a single molecule; examination of new hypotheses regarding the underlying mechanism of pain, tolerance, and other aspects of opioid activity; use of cellular models and animal models to examine mechanisms related to pain; use of state of the art pharmacology, physiology, and molecular biology to examine mechanisms to pain and tolerance; and use of a wide variety and in vitro and in vivo assays to fully evaluate designed ligands. New modalities for the treatment of pain without the side effects of current clinical opioids is a major goal of this Program Project. [unreadable] [unreadable]